ADAM-mediated Shedding in Inflammatory Responses Inflammation is a key process in disease pathogenesis, and leukocyte recruitment and transendothelial migration into inflamed tissues control both initiation and progression of acute and chronic inflammatory diseases. Studies funded by this R01 have demonstrated that proteolysis mediated by two transmembrane proteases, Adam10 and Adam17, controls the inflammatory response. Our data specifically implicate (i) monocyte Adam10 in limiting monocyte emigration into inflamed vessels in vivo; (ii) neutrophil Adam17 in limiting early neutrophil influx into inflammatory sites in vivo through its cleavage of L-selectin; (iii) monocyt Adam17 in promoting monocyte diapedesis between endothelial cells in vitro, and (iv) macrophage Adam17 in promoting the resolution of inflammation. Our overall hypothesis is that cell-, substrate-, and contect-specific cleavage of key inflammatory proteins by Adam10 and Adam17 is critical to regulation of inflammatory responses. The proposed studies will build upon these observations by determining: 1) the in vitro and in vivo mechanisms by which the transmembrane proteases Adam10 and Adam17 modulate inflammatory responses; and 2) establish substrates of Adam10 and Adam17 responsible for regulation monocyte trafficking into and out of inflammatory sites. These studies have the potential to identify biomarkers to recognize patients at risk with chronic inflammatory diseases, and to help determine therapeutic strategies for their treatment. PUBLIC HEALTH RELEVANCE: Limited and specific proteolysis of monocyte and endothelial cell surface proteins represents a rapidly mobilized regulatory mechanism to control the inflammatory response. The proposed studies will determine mechanisms through which two transmembrane enzymes, Adam10 and Adam17, regulate transendothelial cell migration in vitro and in vivo. This research has the potential to identify biomarkers to recognize patients at risk with chronic inflammatory diseases, and to help determine therapeutic strategies for their treatment.